1. Field of the Invention
This invention relates to vesamicol derivatives that have anticholinergic properties.
2. Description of the Related Art
The vesamicol receptor, a cytoplasmically-oriented site on the cholinergic synaptic vesicle, is associated with the vesicular transporter of acetylcholine (reviewed by Marshall and Parsons, 1987). The location of this receptor provides opportunities for the investigation of presynaptic cholinergic phenomena associated with the release and/or storage of acetylcholine.
The prototypical vesamicol receptor ligand 2-(4-phenylpiperidinyl)cyclohexanol (1, vesamicol, AH5183) exhibits nanomolar affinity for this receptor (Bahr and Parsons, 1986). However, vesamicol also exhibits significant alpha-adrenoceptor activity (Estrella et al., 1988), an attribute which limits its usefulness in the study of presynaptic cholinergic function. In an earlier structure-activity study (Rogers et al., 1989), the vesamicol analogs 2a, 2b and 3 were identified as potent ligands for this receptor. In addition to providing new insights into the topography of the vesamicol receptor, these novel analogs also represent lead structures for developing a new generation of potent and selective ligands for this receptor. Although 2b, a pseudo-irreversible ligand, has been used as a lead for developing a number of potentially useful ligands (Jung et al., 1990; Kilbourn et al., 1990), the full implications accompanying the activity of 3 have yet to be realized.
In U.S. Pat. No. 4,522,965 which issued Nov. 12, 1985 to Stanley M. Parsons, a vesamicol derivative is described for use in blocking conduction at the neuromuscular junction in mammals. Parsons notes that it is desirable to produce a more effective compound than vesamicol for blocking presynaptic release of acetylcholine.
In an earlier study, Rogers et al. (1989) noted that the vicinal aminoalcohol functionality was essential for vesamicol-like anticholinergic activity. Furthermore, these authors showed that benzo fused analogs like 2a and 2b were potent inhibitors of vesicular ACh transport. In contrast, those analogs which lacked a cyclohexyl moiety (e.g. 4a, 4b) were found to exhibit substantially diminished activity.
In a subsequent study, we demonstrated that potent noncyclohexyl-containing vesamicol analogs could be obtained by attaching arylethyl substituents onto 4a. Case in point, compound 4c was found to be 59 times more potent than 4a.
Vesamicol has the ability to inhibit both the uptake of Ach into cholinergic synaptic vesicles and quantal release of this neurotransmitter from cholinergic neuron. Vesamicol binds reversibly to a unique cytoplasmically-oriented site, the vesamicol receptor, located on the cholinergic synaptic vesicle (and the prejunctional neuronal membrane) and thus interferes with the aforementioned processes. Given its location, the vesamicol receptor may be a useful presynaptic marker of cholinergic innervation. Such a receptor site would provide a suitable target for the development of radiotracers for mapping cholinergic pathways in vivo.
The study of cholinergic innervation in vivo is potentially of diagnostic value in neurodegenerative disorders such as Alzheimer's disease wherein significant decreases in cholinergic innervation have been detected early in the disease progression (Reisine et al 1978; Rossor et al 1982; Bowen et al 1983; Mountjoy et al 1984). The potential utility of the vesamicol receptor as a presynaptic cholinergic marker has been demonstrated by preliminary characterization of [.sup.3 H]vesamicol binding in the rodent brain (Marien et al 1977; Altar et al 1988). In these studies, the distribution of radiolabelled vesamicol was found to correlate well with other markers of cholinergic innervation. In addition, a significant decrease in cortical [.sup.3 H]vesamicol binding was obtained by lesioning a known cholinergic pathway (Altar et al 1988; Marien et al 1987).
Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with loss of memory and other cognitive functions. Recent epidemiologic studies suggest that 10% of adults over the age of 65 (about 4 million people) may suffer from this disorder.
Progress in the diagnosis and subsequent clinical management of AD has been slowed by the absence of both a reliable diagnostic procedure and an established therapeutic regimen. Currently, a definitive diagnosis of AD can only be made by histopathologic examination of brain tissue. Brain biopsy is not practical in clinical practice. Therefore, patients are subjected to a battery of psychometric, radiologic and chemical tests designed to exclude the presence of other diseases. Only 50% of these diagnoses are found to be accurate at autopsy.
An important feature of AD is that neurons which produce the neurotransmitter acetylcholine (cholinergic neurons) progressively degenerate. More importantly, the extent of this degeneration correlates with the severity of AD. Biochemical markers of cholinergic innervation could be used as reliable indicators of AD. The anticholinergic vesamicol binds selectively to a unique site (the vesamicol receptor) on the cholinergic synaptic vesicle, and thus inhibits the uptake of acetylcholine into the synaptic vesicle.
Radiolabeled ligands for the vesamicol receptor will be clinically useful radiopharmaceuticals for evaluating cholinergic innervation in the living human brain. In conjunction with SPECT, these radioligands which bind selectively to the vesamicol receptor should identify the cholinergic deficit in the Alzheimer's brain.
The art described in this section is not intended to constitute an admission that any patent, publication or other information referred to herein is "prior art" with respect to this invention, unless specifically designated as such. In addition, this section should not be construed to mean that a search has been made or that no other pertinent information as defined in 37 C.F.R. .sctn. 1.56(a) exists.